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High Levels of Soluble Herpes Virus Entry Mediator in Sera of Patients with Allergic and Autoimmune Diseases

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High Levels of Soluble Herpes Virus Entry Mediator in Sera of Patients with Allergic and Autoimmune Diseases EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 35, No. 6, 501-508, December 2003 High levels of soluble herpes virus entry mediator in sera of patients with allergic and autoimmune diseases Hyo Won Jung1, Su Jin La1, Ji Young Kim2 neutrophils and dendritic cells. In three-way MLR, Suk Kyeung Heo1, Ju Yang Kim1, Sa Wang3 mAb 122 and 139 were agonists and mAb 108 had Kack Kyun Kim4, Ki Man Lee5, Hong Rae Cho6 blocking activity. An ELISA was developed to detect Hyeon Woo Lee1, Byungsuk Kwon1 sHVEM in patient sera. sHVEM levels were elevated 1 1,7,8 in sera of patients with allergic asthma, atopic Byung Sam Kim and Byoung Se Kwon dermatitis and rheumatoid arthritis. The mAbs dis- 1 cussed here may be useful for studies of the role The Immunomodulation Research Center and of HVEM in immune responses. Detection of soluble Department of Biological Sciences HVEM might have diagnostic and prognostic value University of Ulsan, Ulsan 680-749, Korea in certain immunological disorders. 2The Immunomics Inc. Ulsan 680-749, Korea Keywords: asthma; atopic; autoimmune diseases; der- 3Department of Microbiology and Immunology matitis; inflammation mediators; rheumatoid arthritis; Indiana University School of Medicine tumor necrosis factor Indianapolis, IN 46202, USA 4Department of Oral Microbiology College of Dentistry, Seoul National University Seoul 110-744, Korea Introduction 5Department of Internal Medicine Members of the tumor necrosis factor receptor Ulsan University Hospital, University of Ulsan (TNFR) superfamily share a similar architecture of Ulsan 682-714, Korea their extracellular domain; this consists of a series of 6Department of Surgery cysteine-rich segments containing 30-40 amino acids Ulsan University Hospital, University of Ulsan with six cysteines in each segment (Mallett et al., Ulsan 682-714, Korea 7 1991). They are involved in the regulation of diverse LSU Eye Center immune functions. Some of the members of this Louisiana State University School of Medicine family regulate signals leading to apoptosis, whereas 2020 Gravier Street New Orleans LA 70112, USA 8 others are involved in lymphocyte activation and Corresponding author: Tel, 82-52-259-2392; differentiation (Locksley et al., 2001; Kwon et al., Fax, 82-52-259-2740; E-mail, [email protected] 2003). The open reading frame of herpes virus entry mediator (HVEM) encodes a 283 amino acid sequence, Accepted 23 October 2003 two perfect TNFR-like cysteine-rich domains, two im- perfect cysteine-rich domains, and a short cytoplasmic Abbreviations: DC, dendritic cell; HVEM, herpes virus entry medi- tail similar to that seen in 4-1BB and CD40 (Mont- ator; GST, glutathione S-transferase; MLR, mixed leukocyte gomery et al., 1996; Kwon et al., 1997). Because an reaction; RA, rheumatoid arthritis; sHVEM, soluble HVEM; SLE, HVEM-Fc fusion protein inhibited proliferation in a systemic lupus erythematosus; TNFR, TNF receptor; TRAF, TNFR mixed lymphocyte reaction using patient lymphocytes associated factor (Harrop et al., 1998), HVEM may either play a direct role in T cell stimulation or bind to a ligand that stimulates T cell proliferation. HVEM is a cellular Abstract mediator of the entry of herpes simplex virus type-1 (HSV-1) (Montgomery et al., 1996) and interacts Herpes virus entry mediator (HVEM) is a newly directly with the HSV virion glycoprotein D (gD) discovered member of the tumor necrosis factor required for entry into HVEM expressing cells (Whit- receptor (TNFR) superfamily that has a role in beck et al., 1997). Hsu et al. (1997) found that the herpes simplex virus entry, in T cell activation and cytoplasmic region of HVEM binds to several mem- in tumor immunity. We generated mAb against bers of the TNFR-associated factor (TRAF) family, HVEM and detected soluble HVEM (SHVEM) in the namely, TRAF1, TRAF2, TRAF3, and TRAF5, but not sera of patients with various autoimmune diseases. to TNFR4 or TRAF6, and that it activates transcription HVEM was constitutively expressed on CD4+ and factors NF-κB and AP-1 (Marsters et al., 1997). As CD8+ T cells, CD19+ B cells, CD14+ monocytes, anti-HVEM mAb are needed for or in-depth studies 502 Exp. Mol. Med. Vol. 35(6), 501-508, 2003 of the role of HVEM in immune responses and in ringer Mannheim, Indianapolis, IN). Cells were se- clinical settings, we generated several mAbs and lected in HAT medium (Boehringer Manheim) using used them to characterize HVEM, and to detect peritoneal macrophages as feeder cells. Antibody soluble HVEM in clinical samples. activity was determined after 10-14 days. ELISA screening Materials and Methods We determined the anti-HVEM activity of supernatants Cells and cell culture of the hybridoma cells by ELISA (Jin et al., 2001). ninety-six-well polypropylene microplates (Falcon, Monocyte-like cell lines HL-60, U937, and THP-1, Oxnard, CA) were coated with 5 mg/ml HVEM-Fc in human CD4+ T cell lines Jurkat and PM-1, human NaHCO overnight at 4oC, blocked with 3% BSA, and embryonic kidney cell line 293, and SP2/0 myeloma 3 incubated with the supernatants. Goat anti-mouse IgG cell line were obtained from the American Type conjugated with horseradish peroxidase (Sigma, St. Culture Collection (ATCC, Manassas, VA). They were Louis, CA) was used as secondary antibody. Plates cultured in either RPMI 1640 or DMEM, supplemented were washed five times with PBS/Tween-20 before with 10% FBS (Hyclone) and antibiotics. Growth was detecting bound antibody by incubation with ABT at 37oC with 5% CO /air. 2 peroxidase substrate (Kirkegaard and Perry Lab, Inc., Gaithersburg, MD). Serum obtained from the mouse Expression and purification of recombinant used to provide the splenocytes was used as a HVEM-GST and HVEM-Fc fusion proteins positive control. The Ig class and subclass of the resulting monoclonal antibodies was determined with We used PCR to amplify the cDNA sequence that the ImmunoPure Monoclonal Antibody Isotyping Kit encodes the ectodomain of HVEM. It was fused in (Pierce, Rockford, IL). frame with the GST-binding domain of glutathionine S-transferase (GST) or with human IgG1 Fc (including hinge, CH2 and CH3 domains). Each of the in-frame Purification of monoclonal antibodies fusions was confirmed by sequencing before being Balb/c mice were primed with Pristane and injected cloned into the PGEX-3 or pcDNA3 expression vector. IP with subcloned hybridoma cells to induce ascites pGEX-3-HVEM-transformed Escherichia coli were formation. The mAbs were purified from the ascites grown to an optical density of 0.6 (A590) before protein fluid by affinity column chromatography with protein expression was induced by the addition of 2 mM (final G-Sepharose (Zymed Lab, Inc, South San Francisco, concentration) isopropyl thiogalactopyranoside (IPTG). CA) (Coligan et al., 1991). The three monoclonal The HVEM-GST fusion protein was purified by two- antibodies (mAbs) used in this work, clones 108, 122 step chromatography with GSH-sepharose 4B. HVEM- and 139, were of isotypes IgG1 (colnes, 108 and 122) Fc fusion protein was produced in NIH 3T3 cells and or IgG2a (clone 139). purified with a protein G column. An automatic peptide sequencer (ABI, Perkin-Elmer, Norwalk) was used to determine N-terminal amino acid sequences. SDS-PAGE and Western blot analysis HVEM-GST was purified by two-step chromatography with GST-sepharose 4B, and used as control for Immunization and fusion Western blot analysis. Lysates (5×107 cells/ml) of A 6-8 week-old female Balb/c mouse (Harlan, India- THP-1 and Jurkat cells were digested in lysis buffer napolis, IN) was injected i.p. with 30 µg HVEM-GST [1% Triton X-100 in 150 mM NaCl and 20 mM fusion protein emulsified with an equal volume of Tris-HCl (pH 8.0)] at 4oC for 30 min. The lysates and Freund's complete adjuvant (Gibco-BRL, Gaithersburg, HVEM-GST were denatured by boiling for 5 min with MD). After two weeks the mouse was injected IP with 0.5% SDS and 1% β-mercaptoethanol, subjected to the same amount of HVEM-GST fusion protein emul- SDS-PAGE, and transferred to nitrocellulose mem- sified with an equal volume of Freund's incomplete branes. The membranes were blocked in reaction adjuvant. Two weeks later the mice received a third buffer (10 mM Tris [pH 7.4], 150 mM NaCl, 10% injection i.v. of 30 µg of HVEM-GST in PBS. Fusion nonfat dried milk, 0.05% Tween-20) for 1 h and of myeloma cells with splenocytes was performed as incubated with anti-HVEM mAb 108 diluted 1:5,000 in described by Kohler and Milstein (1975). SP2/0 were reaction buffer, followed by horse peroxidase-coupled used as fusion partner during exponential growth, with goat anti-mouse IgG (Boehringer Mannheim) diluted more than 95% viability. Primed lymphocytes were 1:10,000. Secondary antibody was detected by in- mixed with myeloma cells at a ratio of 5:1 and fused cubation in ECL reagent (Amersham Biosciences, in 50% (w/v) polyethylene glycol MW 1500 (Boeh- Piscataway, NJ) and exposure to X-ray film (Kodak, Detection of soluble HVEM in sera of patients 503 Rochester, NY). (ICN Biomedicals, Costa Mesa, CA) was then added for an additional 16 h. The cells were harvested, and radioactivity counted. Flow cytometry 293 cells transfected with HVEM-pcDNA3 were stained 48 h after transfection. Cultured cells were also Detection of soluble HVEM (sHVEM) in human serum stained with or without stimulation with anti-CD3 sHVEM was detected by ELISA using 108 as cap- (OKT3; 1 µg/ml) and LPS (100 ng/ml). They were turing mAb, and 122 as detecting mAb. A standard washed twice, resuspended in 1% paraformaldehyde curve was constructed with HVEM-Fc (R & D system, and analyzed by flow-cytometry with a FACScan Minneapolis, MN) as antigen.
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